Coated particles with prolonged release and tablets containing same

ABSTRACT

The invention concerns coated particles with prolonged release, a method for preparing same and multiparticulate tablets comprising said coated particles.

The invention relates to coated particles and more specifically tosustained-release coated granules or granulates, to a process forpreparing them and to multiparticulate tablets comprising said coatedparticles.

Sustained-release multiparticulate forms are well known in the priorart.

These forms exist in particular in unit forms such as gel capsules ormultiparticulate tablets.

The term “multiparticulate tablet” means a tablet comprising, firstly,particles containing at least one active principle, which areindividually coated with a polymer film that modifies the release of theactive principle over a period that can range from 8 to 24 hours, and,secondly, tabletting excipients.

The coated particles are first mixed with the tabletting excipients, themixture then being compressed so as to give a homogeneous unit form.During the compression step, the polymer coating experiences largestresses, which are such that cracks or breaks may appear, resulting inloss and immediate availability of all of the active principle.

The polymer film should thus be flexible enough and deformable enough towithstand compression.

To evaluate the mechanical properties and characteristics of the polymerfilm, parameters such as the breaking strength or the percentage ofelongation may be used. These mechanical characteristics may bedetermined by the methods described in standards DIN 53455 and ISO/RI184.

Acrylic polymers are a family of polymers with deformation propertiesthat allow the preparation of multiparticulate tablets.

In Patent Application EP 1 032 374, the Applicant describes spheroidscomprising, in the core or as a layer, a thermoplastic excipient with apasty to semi-solid consistency at 20° C., and a flexible and deformablefilm whose percentage of elongation is greater than or equal to 50%, andwhich consists of a neutral copolymer of acrylic acid esters, forexample the product sold under the brand name Eudragit® NE30D, thepercentage of elongation of which is 600% and the compressive strengthof which is 8 N m².

Polymers that have mediocre elongation or compressive strengthparameters do not normally absorb the mechanical stresses associatedwith tabletting (International Journal of Pharmaceutics, 143, 13-23(1996)).

Numerous publications describe cellulose-based polymers as being brittleand inelastic. This is the case, for example, for ethylcellulose, theelongation capacity of which is usually less than 15%, which makes itdifficult for it to be used as a coating agent for particles intended tobe compressed (Eur. J. Pharm. Biopharm., 43, 1-8 (1997)).

Studies on ethylcellulose-based free films show that the addition ofplasticizers or of soluble agents to the coating film, and the use of amaturation step under certain temperature and humidity conditions (Int.J. Pharm. 104, 203-213, (1994), Acta Pharm. Technol. 35(4), 232-237,(1989)) can make it possible to improve the properties of films based oncellulose derivatives.

However, this improvement is insufficient. Moreover, the release profileof the active principle is directly influenced by the composition of thecoating film.

It would be particularly advantageous to have available means for makingthem systematically usable for the constitution of coating films,without modifying their composition or having an influence on theiractive principle release profile.

However, to its credit, the Applicant has now found that this aim can beachieved and that it has become possible to obtain sustained-releasecoated particles with a coating consisting of at least onecellulose-based polymer such that the release profile of amultiparticulate tablet based on these particles is identical to that ofthe coated particles before tabletting, the two release profiles beingdetermined under similar working conditions (dissolution medium,apparatus, method), since said particles are given a protective coatingbased on at least one thermoplastic agent with a melting point of from25 to 100° C. applied over the coating based on cellulose-based polymer.

It is considered that two release profiles are similar when thevariation between the means of the values measured for each of theprofiles at each sampling time is less than or equal to plus or minus15% and preferably plus or minus 10%, i.e., in the present case, betweenthe mean value obtained for the coated particles before tabletting andthat obtained for the multiparticulate tablet based on said particles.

If the variation under consideration is greater than 15%, it isconsidered that the release profile is significantly modified.

It follows therefrom that the sustained-release coated particles inaccordance with the invention, which comprise

-   -   a core comprising an active principle and at least one binder,        and    -   a coating film based on at least one cellulose-based polymer,        alone or as a mixture with a plasticizer, are characterized in        that they comprise a protective coating based on at least one        thermoplastic agent with a melting point of from about 25° C. to        about 100° C. and which is applied to the coating film based on        at least one cellulose-based polymer.

The particles in accordance with the invention consist of granules orgranulates, depending on the process for obtaining the active core.

The granulates are obtained by dry or wet granulation and the granulesby mounting the active principle on a neutral support.

The core of the particle comprises at least one active principle chosenfrom those of the group comprising gastrointestinal sedatives, antacids,analgesics, antiinflammatories, coronary vasodilators, peripheral andcerebral vasodilators, antiinfectives, antibiotics, antiviral agents,antiparasitic agents, anticancer agents, anxiolytics, neuroleptics,central nervous system stimulants, antidepressants, antihistamines,antidiarrheal agents, laxatives, dietary supplements, immunodepressants,hypocholesterolemiants, hormones, enzymes, antispasmodics, antianginalagents, medicinal products that affect the heart rate, medicinalproducts used in the treatment of arterial hypertension, antimigraineagents, medicinal products that affect blood clotting, antiepileptics,muscle relaxants, medicinal products used in the treatment of diabetes,medicinal products used in the treatment of thyroid dysfunctions,diuretics, anorexigenic agents, antiasthmatics, expectorants,antitussive agents, mucoregulators, decongestants, hypnotics, antinauseaagents, hematopoietic agents, uricosuric agents, plant extracts andcontrast agents.

This active principle, initially in the form of powder or microcrystals,is used in dry form for the preparation of granulates, and in the formof a solution or a suspension in an aqueous or organic solvent formounting on neutral supports.

Advantageously, the cores comprise a binder for binding the powder orthe microcrystals of active principle and the other possibleconstituents, so as to give particles of a size sufficient to facilitatethe coating operation.

The binder may be chosen from the group especially comprisingcellulose-based polymers, acrylic polymers, povidones, copovidones,polyvinyl alcohols, alginic acid, sodium alginate, starch,pregelatinized starch, sugars and derivatives thereof, guar gum andpolyethylene glycols, and mixtures thereof.

Among the cellulose-based polymers that will advantageously be chosenare ethylcellulose, hydroxypropylcellulose andhydroxypropylmethylcellulose, alone or as a mixture.

Among the acrylic polymers that are advantageously chosen areammoniomethacrylate copolymer, acrylic and methacrylic acid polymers andcopolymers, polyacrylates and polymethacrylates, used alone or as amixture.

The binder is present in proportions that may be up to 15% by weight andpreferably up to 10% by weight relative to the weight of the uncoatedparticles.

The core optionally comprises a diluent and an antistatic agent.

The diluent may be chosen from the group especially comprisingcellulose-based derivatives and preferably microcrystalline cellulose,starches alone, lactose and polyols, and preferentially mannitol.

The core may also be a neutral support consisting of a mixture of starchand sucrose, or alternatively microcrystalline cellulose.

The diluent is present in proportions that may be up to 95% by weightand preferably up to 50% by weight relative to the weight of theuncoated particles. Its role is to increase the total mass of particlesto be coated and to obtain a population of particles of homogeneoussize.

The antistatic agent may be chosen from the group comprising colloidalsilica, especially the product sold under the brand name Aerosil®, andpreferentially precipitated silica, especially the product sold underthe name Syloid® FP244, and micronized or nonmicronized talc, andmixtures thereof.

The antistatic agent is present in proportions that may be up to 10% byweight and preferably up to 3% by weight relative to the weight of theuncoated particles.

It improves the fluidization of the material during the use of afluidized air bed, in particular in the case of powder granulation.

The cores comprising the active principle are then coated with a firstcoating composition.

The coating film thus obtained allows the sustained release of theactive principle.

This coating film consists of at least one cellulose-based polymer,alone or as a mixture with a plasticizer.

Ethylcellulose is preferably chosen among cellulose-based polymers.

This coating film is applied by spraying a solution, a suspension or acolloidal dispersion of this polymer in a solvent, to form a continuousfilm that covers all of the surface of each particle, irrespective ofthe surface state of said particle, in an amount sufficient to allow thesustained release of the active principle over a period that may rangefrom 8 to 24 hours.

The coating polymer is present in proportions that may be up to 50% andpreferably up to 20%, calculated as weight gain relative to the mass ofcores to be coated.

The solvent chosen to spray the cellulose-based polymer may be water, anorganic solvent, such as ethanol, isopropanol or acetone, or a mixtureof solvents.

In this case, the polymer is in the form of a solution, suspension ordispersion, in the solvent or mixture of solvents. It is preferably inthe form of a solution in an organic solvent, preferably in isopropanol.

The coating composition also optionally comprises a pore-forming agent,a plasticizer, a surfactant, an antistatic agent or a lubricant.

The pore-forming agent can modify the release of the active principle,and in particular can accelerate it.

This agent should be soluble in media with a pH of less than or equal to5. It may be chosen, for example, from sugars, polyols, acrylic ormethacrylic acid polymers or copolymers, hydroxylated cellulosederivatives, povidones and polyvinyl alcohols.

The plasticizer is chosen from the group comprising triethyl citrate,acetyltributyl citrate, triacetin, tributyl citrate, diethyl phthalate,polyethylene glycols, polysorbates and mono- and diacetyl glycerides,and mixtures thereof.

Its function is to lower the glass transition temperature of the coatingfilm and to improve its mechanical properties.

It is used in a proportion of up to 40% and preferably between 15% and30%, expressed on a weight basis relative to the dry weight of polymer.

The surfactant is chosen from anionic, cationic, nonionic and amphotericsurfactants.

The antistatic agent optionally used is employed to avoid problemsassociated with static electricity. It is chosen from the groupcomprising micronized or nonmicronized talc, colloidal silica (Aerosil®200), treated silica (Aerosol® R972) and precipitated silica (Syloid®FP244), and mixtures thereof.

It is used in a proportion of up to 10% by weight, preferably between 0%and 3% and even more preferably less than 1% by weight.

The lubricant is chosen from the group comprising magnesium stearate,stearic acid, sodium stearyl fumarate, micronized polyoxyethyleneglycols (micronized Macrogol 6000) and sodium benzoate, and mixturesthereof.

An optional polymer layer may be applied between the core and thefunctional polymer film to insulate the core, comprising the activeprinciple, from the layer of cellulose-based polymer that allows thesustained release of the active principle.

The polymer constituting the optional layer may be chosen from the samepolymers as those used as binder; in particular, it may be identical toor different than the polymer used as binder in the core comprising theactive principle.

The advantage provided by this optional layer is that it allows theactive principle to be insulated from the functional polymer that allowsits sustained release,

-   -   when there is incompatibility between the active principle and        the functional polymer,    -   when the active principle is unstable at the pH of the solution        or suspension used to apply the functional polymer,    -   when the active principle has a high solubility in the solvent        used to apply the functional polymer, which may be the cause of        “migration” of the active principle into the polymer film, thus        making it difficult to obtain sustained release of the active        principle.

The amount of polymer applied is between 1% and 10% and preferablybetween 2% and 5% as weight gain relative to the mass of corescomprising the active principle used.

In accordance with the invention, the layer of cellulose-based polymerallowing the sustained release of the active principle is covered with acoating that protects it.

This protective coating is based on at least one thermoplastic agentwith a melting point of from about 25° C. to about 100° C. andoptionally a lubricant.

The thermoplastic agent is chosen from the group comprising partiallyhydrogenated oils, beeswax, carnauba wax, paraffin waxes, siliconewaxes, fatty alcohols, C₁₂-C₁₈ fatty acids, solid semisyntheticglycerides, glyceryl monoesters, diesters or triesters, polyoxyethyleneglycols and polyoxyethylenated glycosyl glycerides, and mixturesthereof.

The function of the protective coating is to absorb the stresses causedby tabletting, and to avoid deformation, alteration or breaking of thecoating film consisting of the cellulose-based polymer, the function ofwhich is to ensure the sustained release of the active principle.

The thermoplastic agent is used in a proportion that may be up to 100%as weight gain and preferably between 10% and 50% as weight gain,relative to the mass of granulate to be coated.

It is preferably chosen from hydrophilic excipients with ahydrophilic/lipophilic balance (HLB) of greater than 10, so as not tomodify the release profile of the active principle.

The protective coating may also comprise an antistatic agent.

The particle size distribution of the particles in accordance with theinvention allows their use in the manufacture of multiparticulatetablets.

Advantageously, the size of the particles is less than 700 μm, giventhat the size of at least 50% and preferably of at least 70% of theparticles is between 150 and 500 μm, and that the size of less than 15%of the particles is less than 150 μm.

The particle size is determined by the conventional methods, for exampleusing a set of screens of calibrated mesh size, or by laser diffraction.

By virtue of their mechanical properties, the sustained-release coatedparticles thus prepared are particularly suitable for inclusion in theconstitution of multiparticulate tablets.

The multiparticulate tablet in accordance with the invention ischaracterized in that it is based on coated particles in accordance withthe invention, this tablet also comprising a mixture of excipientscomprising

-   -   a disintegrant and/or a swelling agent,    -   at least one diluent,    -   a lubricant, and    -   optionally, an antistatic agent, a permeabilizer, sweeteners,        flavorings and colorants.

The disintegrant is chosen from the group comprising crosslinked sodiumcarboxymethylcellulose, referred to in the art as croscarmellose,crospovidone and mixtures thereof.

The swelling agent is chosen from the group comprising microcrystallinecellulose, starches and modified starches.

The diluent may be chosen from the group comprising cellulosederivatives and preferentially microcrystalline cellulose, lactose andpolyols, and preferentially mannitol.

The lubricant is chosen from the group comprising magnesium stearate,stearic acid, sodium stearyl fumarate, polyoxyethylene glycols(micronized Macrogol 6000) and sodium benzoate, and mixtures thereof.

The lubricant is totally or partially dispersed in the mixture oftabletting excipients and/or sprayed onto the surface of the tablet atthe time of tabletting.

The antistatic agent may chosen from the group comprising colloidalsilica, especially the product sold under the brand name Aerosil®, andpreferentially precipitated silica, especially the product sold underthe name Syloid® FP244, and micronized or nonmicronized talc, andmixtures thereof.

The permeabilizer is chosen from the group especially comprising silicaswith great affinity for aqueous solvents, such as the precipitatedsilica more commonly known under the brand name Syloid®, maltodextrinsand β-cyclodextrins, and mixtures thereof.

It allows the creation of a hydrophilic network that facilitates thepenetration of saliva and thus contributes toward better disintegrationof the tablet.

The sweetener may be chosen from the group especially comprisingaspartame, potassium acesulfame, sodium saccharinate, neohesperidinedihydrochalcone, sucralose and monoammonium glycyrrhizinate, andmixtures thereof.

The flavorings and colorants are those usually used in pharmaceuticalsfor the preparation of tablets.

In the multiparticulate tablets in accordance with the invention, theproportion of the mixture of excipients relative to the coated particlesis from 0.4 to 10 and preferably between 1 and 5 parts by weight, saidmixture of excipients comprising:

-   -   from 1% to 15% and preferably from 2% to 7% by weight of        disintegrant and/or swelling agent,    -   from 30% to 90% and preferably from 40% to 70% by weight,        relative to the mass of the tablet, of diluent,    -   from 0.02% to 2% and preferably from 0.5% to 1% by weight,        relative to the mass of the tablet, of lubricant,    -   from 0.5% to 5% by weight, relative to the mass of the tablet,        of permeabilizer.

In one preferred embodiment, the multiparticulate tablet according tothe invention is an orodispersible tablet that disintegrates in themouth, on contact with the saliva, in less than 60 seconds andpreferably in less than 40 seconds, forming a suspension that is easy toswallow.

The disintegration time corresponds to the duration between the momentthat the tablet is placed in the mouth in contact with the saliva andthe moment of swallowing of the suspension resulting from thedisintegration without chewing of the tablet in contact with the saliva.

The diluent is chosen from soluble agents with binding properties,consisting of polyols of less than 13 carbon atoms and being either inthe form of a directly compressible product with a mean particlediameter of from 100 to 500 μm, or in the form of a powder with a meanparticle diameter of less than 100 μm, these polyols preferably beingchosen from the group comprising mannitol, xylitol, sorbitol andmaltitol, used in the form of a directly compressible product, whereas,in the case where there are at least two soluble diluents with bindingproperties, one is present in the directly compressible form and theother in the form of a powder, the polyol possibly being the same, theproportions of directly compressible polyol and of polyol powder beingfrom 99/1 to 20/80 and preferably from 80/20 to 20/80.

A subject of the invention is also a process for preparingsustained-release coated particles.

The process under consideration comprises, in accordance with theinvention, the following steps:

-   -   preparation by wet granulation or mounting on neutral supports,        of a core comprising the active principle,    -   coating of the cores thus obtained by spraying a coating        composition consisting of at least one cellulose-based polymer,    -   coating of the coated particles thus obtained by spraying with a        protective coating composition based on an excipient of        thermoplastic type,    -   drying.

According to this embodiment, the successive steps of the process may beperformed in different machines or in the same machine.

In a first advantageous embodiment, the cores comprising the activeprinciple are prepared by granulation according to the following steps:

-   -   dry-mixing of the active principle in the form of powder or        microcrystals, optionally with the diluent and an antistatic        agent,    -   granulation of the mixture obtained by spraying with a solution        of the binder,    -   drying.

For the granulation, a high-energy granulator, a planetary mixer or afluidized air bed is advantageously used.

In the case of granulation in a fluidized air bed, the powder mixturecontaining the active principle and, possibly, the diluent and theantistatic agent, is introduced into the machine and then granulated byspraying onto said powder mixture a solution or suspension of excipientscomprising at least one binder.

According to another advantageous embodiment, the polymer used duringthe granulation step and the polymer used during the coating step areidentical. In this case, the granulation step differs from the coatingstep by different parameters, such as the spraying flow rate of theexcipient mixture and the atomization pressure of said mixture.

Thus, during the granulation step, the spraying flow rate of excipientsuspension is higher than during the coating step, whereas theatomization pressure of the excipient suspension is lower during thegranulation step than during the coating step.

In practice, at the laboratory scale in a fluidized air bed machine, forexample of the Glatt CPCG3 type, the spraying flow rate of the excipientmixture is, during the granulation step, from 15 to 30 grams/minute andthe atomization pressure is from 1 to 2.5 bar.

During the coating step, the spraying flow rate of the coatingsuspension is from 10 to 25 grams/minute, while the atomization pressureis from 1.5 to 3 bar.

Advantageously, a proportion of from 10% to 30% of the mixture ofexcipients is sprayed during the granulation step, the remainder to 100%being sprayed during the coating step.

In a second embodiment of the cores comprising the active principle,they are prepared by mounting on neutral supports according to thefollowing steps:

-   -   spraying onto neutral supports a solution or a suspension of the        active principle, containing the dissolved binder,    -   drying.

The cores thus obtained are then coated by successive spraying of thevarious coating compositions, and then dried.

The polymer coating consisting of a cellulose-based derivative issprayed in the form of a solution, a suspension or a colloidaldispersion.

The thermoplastic excipient may be applied by spraying in the form of asolution in an aqueous or organic solvent.

In one particular embodiment, the thermoplastic excipient may be heatedto a temperature above its melting point, and then sprayed in liquidform without solvent.

In this case, a thermostatically regulated spraying device that makes itpossible to avoid obstructing the tubes is installed.

All the steps of the process in accordance with the invention may beperformed in a sugar-coating turbomixer, in a perforated turbomixer orin a fluidized air bed.

In one preferred embodiment of the process in accordance with theinvention, all the steps of preparation of the active core and ofcoating are performed in a fluidized air bed.

The fluidized air bed is equipped with a spraying nozzle whose sprayingposition and orientation may be chosen. The spraying is designated bythe terms of the art “top spray”, “bottom spray” or “tangential spray”.

This choice makes it possible to control the growth kinetics of theparticles and to avoid phenomena of adhesion, associated with the natureof the active principle and with the composition of the sprayed binderor coating composition, and various process parameters (for exampletemperature, air pressure or flow rate of solution).

The invention also relates to a process for preparing multiparticulatetablets comprising the sustained-release coated particles.

This process includes, in accordance with the invention, the followingsteps:

-   -   dry-mixing of the coated particles, obtained according to the        process described above, with the tabletting excipients,    -   compression of the mixture thus obtained, to make a unit form.

The compression of the mixture may be performed on an alternating orrotary tabletting machine.

The stresses exerted during the compression step may range from 5 kN to50 kN and preferably from 5 kN to 15 kN.

The hardness of the tablets thus obtained is preferably from 1 to 10 kpand more preferably from 1 to 5 kp, measured according to the method ofthe European Pharmacopea (2.9.8), 1 kp being equal to 9.8 N.

Preferably, the hardness of the multiparticulate tablet is adaptedfirstly so as to obtain a friability of less than 2%, measured accordingto the method of the European Pharmacopea, while at the same timemaintaining a dissolution profile identical to that of the coatedparticles, and secondly so as to obtain a disintegration time in themouth of less than or equal to 60 seconds and preferably less than orequal to 40 seconds.

The tablets may have a diameter of from 6 mm to 17 mm. They may beround, oval or oblong in shape, having a flat or concave surface, andmay optionally be engraved.

In the case of orodispersible tablets, “polo” punches may be used, i.e.punches for obtaining round, flat tablets with concavity at the centerof the two faces.

The tablets have a mass preferably of between 0.1 and 2.0 grams.

The invention will be understood more clearly with the aid of theexamples of preparation of the coated particles and of themultiparticulate tablets in accordance with the invention. Theseexamples are given solely as illustrations and advantageous embodimentsof the invention and do not in any way constitute a limitation thereof.

EXAMPLE 1

Coated granulates comprising oxycodone HCl as active principle.

Granulation

500 grams of oxycodone HCl are mixed with 15 grams of Syloid® 244 FP[i.e. 3% (w/w) relative to the mass of oxycodone HCl].

The mixture of powders is granulated in a planetary mixer using awetting solution consisting of ethylcellulose N7, at a concentration of8% (w/w) in isopropanol.

The grain formed is oven-dried at 45° C. for 5 hours and then screenedthrough a 0.9 mm diameter screen.

Coating

The coating operation is performed in a Glatt GPCG-3 fluidized air bedequipped with a Würster insert (“bottom spray”).

The mass obtained is spray-coated with the same solution as in thepreceding step.

An amount of polymer corresponding to 42% (w/w), calculated as weightgain relative to the mass of starting uncoated granulates, is applied.

The particle size distribution of the coated particles E1 is given inTable 1. TABLE 1 Mesh aperture E1 >0.710 mm 20.7% 0.600 mm-0.710 mm11.5% 0.500 mm-0.600 mm 12.5% 0.355 mm-0.500 mm 17.4% 0.180 mm-0.355 mm25.8% 0.075 mm-0.180 mm 7.9% <0.075 mm 4.2%

The yield by mass is 96.32% (w/w). The composition of the coatedgranulates E1 is given in Table 2: TABLE 2 % (w/w) Oxycodone HCl 65.46Syloid ® 244FP 1.96 Ethylcellulose N7 32.60 Isopropyl alcohol —

EXAMPLE 2

Orodispersible multiparticulate tablets comprising oxycodone HCl asactive principle.

Compression

A “Manesty F3 press” alternating tabletting machine equipped with 8 mmdiameter Polo punches is used. The coated granulates obtained accordingto example 1 are mixed with tabletting excipients.

Two types of tablet are prepared, T1 and T2, respectively, comprisingdifferent relative proportions of coated oxycodone HCl granulates.

The tablets T1 and T2 have respective doses of 19.8 and 10 mg ofoxycodone HCl, according to the indications of Table 3: TABLE 3 T1 T2Constituents % by weight % by weight Oxycodone HCl-coated 19.8 10.0granulates Mannitol 300 33.2 37.3 Mannitol 60 33.2 37.3 Crospovidone 9.810.0 Orange flavoring 1.0 1.0 Syloid ® 244FP 1.0 0.4 Magnesium stearate2.0 2.0 Aspartame — 2 Total 100 100

The tablets T1 and T2 have the characteristics indicated in Table 4:TABLE 4 T1 T2 Theoretical proportion 20% 10% granulates/tablet Weight(mg) 156.0 308.6 Hardness (kP) 1.5 1.5 Friability not not determineddetermined Disintegration time 10-15 sec 15 sec in the mouth

A comparative dissolution profile between the coated granulates ofexample 1 (designated as E1) and the tablets of formulae T1 and T2 areestablished under the following conditions:

-   -   apparatus: USP type II    -   paddle speed: 100 rpm    -   volume: 900 ml    -   temperature: 37.0° C.±0.5° C.    -   detection: direct UV spectrophotometry at 244 nm    -   dissolution medium: 0.01 N HCl (pH=2).

The recorded results are collated in Table 5: TABLE 5 Oxycodone released(% (w/w)) Time (hours) E1 T1 T2 0.5 16 37 43 1 30 53 58 2 47 74 78 4 6992 95 6 78 95 98 8 81 96 99 10 81 96 99Conclusion:

It is possible to deduce from the results collated in Table 5 that thecompression causes rupture of the ethylcellulose film, which results inaccelerated release of the active principle.

The result of this is that the mechanical properties of the coating filmare not suitable for compression in the form of a sustained-releaseorodispersible tablet.

EXAMPLE 3

Coated granules comprising theophylline as active principle.

Mounting on Neutral Supports

The operation is performed in a Glatt GPCG-3 fluidized air bed equippedwith a Würster insert (“bottom spray”).

1500 grams of theophylline are suspended in 4500 g of isopropanol, intowhich have been predissolved 262.5 grams of PVP K29, i.e.polyvinylpyrrolidone or povidone, K29, the K value expressing the meanmolecular weight of the povidones calculated from the relative viscosityin water and defined in the European Pharmacopea (section 2.2.1.2 and2.3.2.1), used as binder [i.e. 17% (w/w) relative to the mass oftheophylline].

1500 grams of neutral supports consisting of starch and sucrose, ofabout 250-350 μm in size, are introduced into the fluidized air bed.

Said alcoholic suspension containing the theophylline is sprayed ontothe neutral supports.

Coating with Ethylcellulose N7

The operation is performed in a Glatt GPCG-3 fluidized air bed equippedwith a Würster insert (“bottom spray”).

600 grams of granules obtained in the preceding step are spray-coatedwith a solution of ethylcellulose N7 in isopropyl alcohol as prepared inexample 1, also containing micronized talc, corresponding to 10% (w/w),relative to the dry mass of polymer.

An amount of polymer corresponding to 5% (w/w), calculated as weightgain relative to the mass of granules to be coated, is applied.

The particle size distribution of the coated particles obtained anddesignated by E2 is given in Table 6: TABLE 6 Mesh aperture E2 >0.500 mm6.6% 0.425 mm-0.500 mm 46.2% 0.355 mm-0.425 mm 38.2% 0.250 mm-0.355 mm9.0%Protective Overcoating

The operation is performed in a Glatt GPCG-3 fluidized air bed equippedwith a Würster insert (“bottom spray”).

The coated granules E2 obtained in the preceding step are spray-coatedwith an aqueous solution of PEG 4000 also containing micronized talccorresponding to 10% (w/w), relative to the dry mass of PEG.

The protective coating is applied in an amount corresponding to 20%(w/w), calculated as weight gain relative to the mass of granules E2.

The particle size distribution of the coated particles E3 obtained byapplying the protective coating to the granules E2 is given in Table 7:TABLE 7 Mesh aperture E3 >0.500 mm 15.8% 0.425 mm-0.500 mm 41.2% 0.355mm-0.425 mm 38.4% 0.250 mm-0.355 mm 4.6%

A comparative dissolution profile between the coated granules E2 and E3is established under the following conditions:

-   -   apparatus: USP type II    -   paddle speed: 100 rpm    -   volume: 900 ml    -   temperature: 37.0° C.±0.5° C.    -   detection: direct UV spectrophotometry at 272 nm    -   dissolution medium: 0.01 N HCl (pH=2).

The recorded results are collated in Table 8: TABLE 8 Theophyllinereleased (% (w/w)) Time (hours) E2 E3 1 12 10 2 21 16 4 36 34 6 48 49 857 60 10 63 68Conclusion

From the examination of the results collated in Table 8, it is seen thatthe application of the protective coating to the coated granules E2 doesnot significantly modify their dissolution profile.

EXAMPLE 4

Orodispersible tablets comprising theophylline as active principle.

Compression

A “Manesty F3 press” alternating tabletting machine equipped with 12 mmdiameter Polo punches is used. The coated granules obtained according toexample 3 are mixed with tabletting excipients, according to the twocompositions indicated in Table 9, giving tablets T3 and T4 aftercompression. TABLE 9 T3 T4 Constituents % by weight % by weightTheophylline-coated 35 35 granules E2 or E3 Mannitol 300 26.5 26.5Mannitol 60 26.5 26.5 Crospovidone 10.0 10.0 Flavoring — — Syloid ®244FP 0.5 0.5 Magnesium stearate 1.0 1.0 Aspartame — —

The characteristics of the orodispersible multiparticulate tablets T3and T4 are given in Table 10: TABLE 10 Characteristics T3 T4 Dose ofactive substance of 80 70 the tablet (mg) Tablet weight (mg) 588.0 622.0Hardness (kP) 3.8 3.1 Friability (%) 5.6 0.5 Disintegration time in the29 35 mouth (seconds)

A comparative dissolution profile under the conditions of example 3 isestablished between the multiparticulate orodispersible tablets T3 andT4 containing, respectively, the coated granules E2 and E3.

The recorded results are collated in Table 11: TABLE 11 Theophyllinereleased (% (w/w)) Time (hours) T3 (E2) T4 (E3) 1 51 (12) 16 (10) 2 67(21) 24 (16) 4 83 (36) 43 (34) 6 91 (48) 55 (49) 8 95 (57) 63 (60) 10 98(63) 69 (68)Conclusion

Examination of the results collated in Table 11 makes it possible todeduce that the protective coating significantly improves the mechanicalproperties of the ethylcellulose N7 film in terms of compressivestrength.

EXAMPLE 5

Orodispersible tablets comprising theophylline as active principle areprepared.

Compression

A “Manesty F3 press” alternating tabletting machine equipped with 12 mmdiameter Polo punches is used. The coated granules E3 obtained accordingto example 3 are mixed with tabletting excipients according to theindications of Table 12, giving multiparticulate tablets designated asT5: TABLE 12 T5 Constituents % by weight Theophylline-coated 20 granulesE3 Mannitol 300 32.8 Mannitol 60 32.8 Crospovidone 10.0 Flavoring 1.0Syloid ® 244FP 0.5 Magnesium stearate 1.0 Aspartame 2.0

The orodispersible multiparticulate tablets T5 have the characteristicsresulting from Table 13: TABLE 13 T5 Dose of active substance of the 25mg tablet (mg) Weight (mg) 555.0 Hardness (kP) 2.5 Friability (%) 0.6Disintegration time in the mouth 26 (seconds)

The comparative dissolution profile under the conditions of example 3 isestablished between the coated granules E3 and the orodispersiblemultiparticulate tablets T5 containing said coated granules.

The recorded results are collated in Table 14: TABLE 14 Theophyllinereleased (% (w/w)) Time (hours) T5 (E3) 1 21 (12) 2 30 (21) 4 43 (36) 652 (48) 8 60 (57) 10 65 (63)

A comparative dissolution profile of the orodispersible multiparticulatetablets T5 is established in various dissolution media, with respectivepH values of 1.2, 4.5 and 6.8:

The recorded results are collated in Table 15: TABLE 15 TimeTheophylline released (% (w/w)) (hours) pH 1.2 pH 4.5 pH 6.8 1 (21) 2122 2 (30) 31 31 4 (43) 44 44 6 (52) 53 54 8 (60) 60 62 10 (65) 66 68Conclusion

From examination of the results collated in Table 15, it is possible toconclude that the protective coating significantly improves themechanical properties of the ethylcellulose N7 film in terms ofcompressive strength.

It is also possible to see that the profiles obtained are independent ofthe pH of the medium in which the dissolution is performed.

EXAMPLE 6

To evaluate the differences existing between the compressive strengthsin the case of the cellulose-based polymers, on the one hand, and theacrylic polymers, on the other hand, the same test as in examples 3 and4 is carried out, using as coating polymer a polyacrylate known underthe brand name Eudragit® NE30D sold by Röhm.

Coating with Eudragit® NE30D

The operation is performed in a Glatt GPCG-3 fluidized air bed equippedwith a Würster insert (“bottom spray”).

750 grams of granules obtained after mounting on neutral supports ofexample 3 are spray-coated with an aqueous dispersion of Eudragit®NE30D, diluted to 20% (w/w), also containing micronized talc, in anamount corresponding to 10% (w/w), relative to the dry mass of polymer.

An amount of polymer corresponding to 5% (w/w), calculated as weightgain relative to the mass of granules to be coated, is applied.

After coating, an additional step of maturation of the film at 60° C.for 2 hours is performed.

Particles designated as E4 are thus obtained, the particle sizedistribution of which is given in Table 16: TABLE 16 Mesh apertureE4 >0.500 mm 20.6% 0.425 mm-0.500 mm 46.2% 0.355 mm-0.425 mm 26.4% 0.250mm-0.355 mm 6.8%Application of a Protective Coating

The operation is performed in a Glatt GPCG-3 fluidized air bed equippedwith a Würster insert (“bottom spray”).

The coated granules E4 obtained in the preceding step are spray-coatedwith an aqueous solution of PEG 4000 also containing micronized talc, ina proportion corresponding to 10% (w/w) relative to the dry mass of PEG.

An amount of protective coating corresponding to 20% (w/w), calculatedas weight gain relative to the mass of granule E4, is applied.

Coated particles E5 are thus obtained, the particle size distribution ofwhich is given in Table 17: TABLE 17 Mesh aperture E5 >0.600 mm 4.2%0.500 mm-0.600 mm 23.6% 0.425 mm-0.500 mm 43.2% 0.355 mm-0.425 mm 24.2%0.250 mm-0.355 mm 4.8%

A comparative dissolution profile is established between the coatedgranules E4 and E5 under the conditions of example 3.

The recorded results are collated in Table 18: TABLE 18 Theophyllinereleased (% (w/w)) Time (hours) E4 E5 1 34 40 2 49 57 4 66 74 6 75 84 881 90 10 86 94Conclusion

From examination of the data collated in Table 18, it is seen that theapplication of a protective coating to the granules E4 does notsignificantly modify their dissolution profile.

EXAMPLE 7

Orodispersible multiparticulate tablets comprising theophylline asactive principle

Compression

A “Manesty F3 press” alternating tabletting machine equipped with 12 mmdiameter Polo punches is used. The coated granules E4 and E5 obtainedaccording to example 6 are mixed with tabletting excipients according tothe composition of Table 19, and tablets T6 and T7 corresponding,respectively, to the coated granulates E4 and E5 are obtained: TABLE 19T6 T7 % by weight % by weight Theophylline-coated 35 35 granulesMannitol 300 26.5 26.5 Mannitol 60 26.5 26.5 Crospovidone 10.0 10.0Flavoring — — Syloid ® 244FP 0.5 0.5 Magnesium stearate 1.0 1.0Aspartame — —

The characteristics of the tablets T6 and T7 are collated in Table 20:TABLE 20 T6 T7 Dose of active substance of the 100 70 tablet (mg) Weight(mg) 680.0 583.0 Hardness (kP) 4.2 3.3 Friability (%) 0.8 0.5Disintegration time in the mouth 14 35 (seconds)

A comparative dissolution profile is established under the conditions ofexample 3, between the multiparticulate orodispersible tablets T6 andT7, containing the coated granules E4 and E5, respectively. The recordedresults are collated in Table 21: TABLE 21 Theophylline released (%(w/w)) Time (hours) T6 (E4) T7 (E5) 1 46 (34) 48 (40) 2 65 (49) 66 (57)4 82 (66) 83 (74) 6 90 (75) 92 (84) 8 94 (81) 98 (90) 10 97 (86) 100(94)Conclusion

From examination of the data collated in Table 21, it is found that theprotective coating does not improve the mechanical properties of thefilm formed with Eudragit® NE30D, which is already flexible anddeformable. This is attested by the low variation observed between thedissolution profiles of the orodispersible tablets T6 and T7 containingthe coated granules E4 and E5, respectively.

EXAMPLE 8

Compression

A “Manesty F3 press” alternating tabletting machine equipped with 12 mmdiameter Polo punches is used. The coated granules E5 obtained accordingto example 6 are mixed with tabletting excipients according to thecomposition of Table 22, in which the multiparticulate tablets obtainedare designated as T8: TABLE 22 T8 % by weight Theophylline-coated 20granules E5 Mannitol 300 32.8 Mannitol 60 32.8 Crospovidone 10.0Flavoring 1.0 Syloid ® 244FP 0.5 Magnesium stearate 1.0 Aspartame 2.0

The characteristics of the orodispersible multiparticulate tablets T8are collated in Table 23: TABLE 23 T8 Dose of active substance of the 40tablet (mg) Weight (mg) 580.0 Hardness (kP) 2.7 Friability (%) 0.4Disintegration time in the mouth 27 (seconds)

A comparative dissolution profile is established under the conditions ofexample 3, between the coated granules E5 and the orodispersible tabletsT8, containing said coated granules E5.

The recorded results are collated in Table 24: TABLE 24 Theophyllinereleased (% (w/w)) Time (hours) T8 (E5) 1 45 (40) 2 65 (57) 4 85 (74) 695 (84) 8 100 (90) 10 100 (94)

A comparative dissolution profile of the orodispersible multiparticulatetablets T8 is moreover established in three dissolution media, of pH1.2, 4.5 and 6.8, respectively.

The results are given in Table 25: TABLE 25 Time Theophylline released(% (w/w)) (hours) pH 1.2 pH 4.5 pH 6.8 1 (45) 45 46 2 (65) 64 65 4 (85)84 84 6 (95) 94 93 8 (100)  100 99 10 (100)  100 100Conclusion

From examination of the results collated in Table 25, it is seen thatthe dissolution profile is not significantly modified by the compressionand that the profiles obtained are independent of the pH of the mediumin which the dissolution is performed.

1. A multiparticulate tablet comprising: a disintegrant and/or aswelling agent, at least one diluent, and a lubricant, wherein thetablet is based on sustained-release coated particles comprising: a corecomprising an active principle and at least one binder, and a coatingfilm consisting of at least one cellulosic polymer, alone or as amixture with a plasticizer, and a protective coating based on at leastone thermoplastic agent with a melting point of from about 25° C. toabout 100° C. and which is applied to the coating film based on at leastone cellulosic polymer, said thermoplastic agent being chosen from thegroup comprising partially hydrogenated oils, beeswax, carnauba wax,paraffin waxes, silicone waxes, fatty alcohols, C₁₂-C₁₈ fatty acids,solid semisynthetic glycerides, glyceryl monoesters, diesters ortriesters, polyoxyethylene glycols and polyoxyethylenated glycosylglycerides, and mixtures thereof.
 2. The multiparticulate tablet ofclaim 1, wherein the protective coating of the sustained-release coatedparticles is chosen from excipients whose hydrophilic/lipophilic balance(HLB) is greater than
 10. 3. The multiparticulate tablet of claim 1,further comprising a binder, a permeabilizer, sweeteners, flavorings andcolorants, wherein the protective coating of the coated particlescomprises an antistatic agent and a lubricant.
 4. The multiparticulatetablet of claim 1, wherein the proportion of excipients mixture relativeto the coated particles is from 0.4 to 10 and preferably from 1 to 5parts by weight.
 5. The multiparticulate tablet of claim 1, wherein thetablet disintegrates in a mouth on contact with saliva in less than 60seconds and preferably in less than 40 seconds, forming a suspensionthat is easy to swallow.
 6. The multiparticulate tablet of claim 5,wherein the tablet comprises at least one disintegrant, a diluent, alubricant and optionally a swelling agent, a permeabilizer, sweetenersand flavorings.
 7. The multiparticulate tablet of claim 5, wherein thediluent is chosen from soluble agents with binding properties,consisting of a polyol of less than 13 carbon atoms and being either inthe form of a directly compressible product with a mean particlediameter of from 100 to 500 μm, or in the form of a powder with a meanparticle diameter of less than 100 μm, this polyol preferably beingchosen from the group comprising mannitol, xylitol, sorbitol andmaltitol, used in the form of a directly compressible product, whereas,in the case where there are at least two soluble diluents with bindingproperties, one is present in the directly compressible form and theother in the form of a powder, the polyol possibly being the same, theproportions of directly compressible polyol and of polyol powder beingfrom 99/1 to 20/80 and preferably from 80/20 to 20/80.
 8. Themultiparticulate tablet of claim 1, wherein the coated particlescomprise at least one active principle chosen from those of the groupcomprising gastrointestinal sedatives, antacids, analgesics,antiinflammatories, coronary vasodilators, peripheral and cerebralvasodilators, antiinfectives, antibiotics, antiviral agents,antiparasitic agents, anticancer agents, anxiolytics, neuroleptics,central nervous system stimulants, antidepressants, antihistamines,antidiarrheal agents, laxatives, dietary supplements, immunodepressants,hypocholesterolemiants, hormones, enzymes, antispasmodics, antianginalagents, medicinal products that affect the heart rate, medicinalproducts used in the treatment of arterial hypertension, antimigraineagents, medicinal products that affect blood clotting, antiepileptics,muscle relaxants, medicinal products used in the treatment of diabetes,medicinal products used in the treatment of thyroid dysfunctions,diuretics, anorexigenic agents, antiasthmatics, expectorants,antitussive agents, mucoregulators, decongestants, hypnotics, antinauseaagents, hematopoietic agents, uricosuric agents, plant extracts andcontrast agents.
 9. The multiparticulate tablet of claim 1, wherein thebinder included in the constitution of the coated particles is chosenfrom the group comprising cellulosic polymers, acrylic polymers,povidones, copovidones, polyvinyl alcohols, alginic acid, sodiumalginate, starch, pregelatinized starch, sugars and derivatives thereof,guar gum and polyethylene glycols, and mixtures thereof.
 10. Themultiparticulate tablet of claim 1, wherein: the core of the coatedparticles comprises a diluent and an antistatic agent, the cellulosicpolymer borne by the coated particles is ethylcellulose, the coatingfilm of the coated particles comprises a pore-forming agent, aplasticizer, a surfactant, an antistatic agent and a lubricant, and apolymer layer is applied between the core and the functional polymerfilm borne by the coated particles.
 11. The multiparticulate tablet ofclaim 1, wherein the diameter of the coated particles is from 150 to 700μm, given that the diameter of at least 50% and preferably of at least70% of the particles is between 150 and 500 μm, and that the diameter ofless than 15% of the particles is less than 150 μm.
 12. A method forpreparing coated particles borne by the multiparticulate tablet of claim1, the method comprising: (a) preparing by wet granulation or mountingon neutral supports, of a core comprising the active principle, (b)coating of the cores thus obtained by spraying a coating compositionconsisting of at least one cellulosic polymer, (c) coating of the coatedparticles thus obtained by spraying with a protective coatingcomposition consisting of an excipient of thermoplastic type, dissolvedin an aqueous solvent devoid of organic solvent, (d) drying.
 13. Amultiparticulate tablet comprising a disintegrant and/or a swellingagent, at least one diluent, a lubricant, and an antistatic agent, apermeabilizer, sweeteners, flavorings and colorants, wherein the tabletis based on sustained-release coated particles comprising a corecomprising an active principle and at least one binder, and a coatingfilm consisting of at least one cellulosic polymer, alone or as amixture with a plasticizer, and a protective coating based on at leastone thermoplastic agent with a melting point of from about 25° C. toabout 100° C. and which is applied to the coating film based on at leastone cellulosic polymer, said thermoplastic agent being chosen from thegroup comprising partially hydrogenated oils, beeswax, carnauba wax,paraffin waxes, silicone waxes, fatty alcohols, C₁₂-C₁₈ fatty acids,solid semisynthetic glycerides, glyceryl monoesters, diesters ortriesters, polyoxyethylene glycols and polyoxyethylenated glycosylglycerides, and mixtures thereof.
 14. The multiparticulate tablet ofclaim 13, wherein the protective coating of the sustained-release coatedparticles is chosen from excipients whose hydrophilic/lipophilic balance(HLB) is greater than
 10. 15. The multiparticulate tablet of claim 1,further comprising a binder, a permeabilizer, sweeteners, flavorings andcolorants and in that the protective coating of the coated particlescomprises an antistatic agent and a lubricant.
 16. The multiparticulatetablet of claim 13, wherein the proportion of excipients mixturerelative to the coated particles is from 0.4 to 10 and preferably from 1to 5 parts by weight.
 17. The multiparticulate tablet of claim 13,wherein the tablet disintegrates in a mouth on contact with saliva inless than 60 seconds and preferably in less than 40 seconds, forming asuspension that is easy to swallow.
 18. The multiparticulate tablet ofclaim 16, wherein the tablet comprises at least one disintegrant, adiluent, a lubricant and optionally a swelling agent, a permeabilizer,sweeteners and flavorings.
 19. The multiparticulate tablet of claim 18,wherein the diluent is selected from soluble agents with bindingproperties, consisting of a polyol of less than 13 carbon atoms andbeing either in the form of a directly compressible product with a meanparticle diameter of from 100 to 500 μm, or in the form of a powder witha mean particle diameter of less than 100 μm, this polyol preferablybeing chosen from the group comprising mannitol, xylitol, sorbitol andmaltitol, used in the form of a directly compressible product, whereas,in the case where there are at least two soluble diluents with bindingproperties, one is present in the directly compressible form and theother in the form of a powder, the polyol possibly being the same, theproportions of directly compressible polyol and of polyol powder beingfrom 99/1 to 20/80 and preferably from 80/20 to 20/80.
 20. Themultiparticulate tablet of claim 13, wherein the coated particlescomprise at least one active principle selected from those of the groupconsisting of gastrointestinal sedatives, antacids, analgesics,antiinflammatories, coronary vasodilators, peripheral and cerebralvasodilators, antiinfectives, antibiotics, antiviral agents,antiparasitic agents, anticancer agents, anxiolytics, neuroleptics,central nervous system stimulants, antidepressants, antihistamines,antidiarrheal agents, laxatives, dietary supplements, immunodepressants,hypocholesterolemiants, hormones, enzymes, antispasmodics, antianginalagents, medicinal products that affect the heart rate, medicinalproducts used in the treatment of arterial hypertension, antimigraineagents, medicinal products that affect blood clotting, antiepileptics,muscle relaxants, medicinal products used in the treatment of diabetes,medicinal products used in the treatment of thyroid dysfunctions,diuretics, anorexigenic agents, antiasthmatics, expectorants,antitussive agents, muco-regulators, decongestants, hypnotics,antinausea agents, hematopoietic agents, uricosuric agents, plantextracts and contrast agents.
 21. The multiparticulate tablet of claim15, wherein the binder included in the constitution of the coatedparticles is chosen from the group comprising cellulosic polymers,acrylic polymers, povidones, copovidones, polyvinyl alcohols, alginicacid, sodium alginate, starch, pregelatinized starch, sugars andderivatives thereof, guar gum and polyethylene glycols, and mixturesthereof.
 22. The multiparticulate tablet of claim 13, wherein: the coreof the coated particles comprises a diluent and an antistatic agent, thecellulosic polymer borne by the coated particles is ethylcellulose, thecoating film of the coated particles comprises a pore-forming agent, aplasticizer, a surfactant, an antistatic agent and a lubricant, and apolymer layer is applied between the core and the functional polymerfilm borne by the coated particles.
 23. The multiparticulate tablet ofclaim 13, wherein the diameter of the coated particles is from 150 to700 μm, given that the diameter of at least 50% and preferably of atleast 70% of the particles is between 150 and 500 μm, and that thediameter of less than 15% of the particles is less than 150 μm.
 24. Amethod for preparing coated particles borne by the multiparticulatetablet of claim 13, the method comprising: (a) preparing by wetgranulation or mounting on neutral supports, of a core comprising theactive principle, (b) coating of the cores thus obtained by spraying thecoating composition consisting of at least one cellulosic polymer, (c)coating of the coated particles thus obtained by spraying with aprotective coating composition consisting of an excipient ofthermoplastic type, dissolved in an aqueous solvent devoid of organicsolvent, (d) drying.